Resveratrol regulates the expression of NHE-1 by repressing its promoter activity: critical involvement of intracellular H2O2 and caspases 3 and 6 in the absence of cell death.
Na(+)/H(+) exchanger-1 (NHE-1) overexpression is associated with carcinogenesis and is an attractive target for intervention. We report that the chemopreventive agent resveratrol (RSV) downregulates NHE-1 in a caspase-dependent manner without inducing cell death. Resveratrol triggered early activation of caspase 3 and late activation of caspase 6, which were not inter-dependent. Whereas, caspase 3 activation appeared to be a direct effect of resveratrol, caspase 6 activation was mediated via intracellular hydrogen peroxide production and iron. Moreover, downregulation of NHE-1 expression was a function of resveratrol-induced repression of NHE-1 gene promoter activity. RNAi-mediated silencing of caspase 3 or 6 blocked the effect of resveratrol on NHE-1 expression, however the effect on NHE-1 promoter was observed at different phases of promoter repression with caspase 3 controlling the early phase (4-12 h) and caspase 6 regulating the late phase (12-24 h). Scavenging hydrogen peroxide or iron only reversed the late phase of resveratrol-induced NHE-1 promoter repression. Finally, an AP2 binding region within NHE-1 gene promoter was identified as the target of resveratrol. Collectively, these data could explain the anti-cancer activity of resveratrol in the light of the association of increased NHE-1 expression with carcinogenesis.
Jhumka
Ziyad
Z
Department of Biochemistry, Yong Loo Lin School of Medicine, Singapore.
Pervaiz
Shazib
S
Clément
Marie-Veronique
MV
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D053178:Caspase 6 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D000077185:Resveratrol; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis* / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D017923:Sodium-Hydrogen Exchangers; D013267:Stilbenes; C069139:growth factor-activatable Na-H exchanger NHE-1; D006861:Hydrogen Peroxide; D053148:Caspase 3; D053178:Caspase 6; D000077185:Resveratrol